Small Volatile Inhibitors Targeting LncRNA in Radioresistant Non-small Cell Lung Cancer

Background and objectives: Radiotherapy is the most crucial nonsurgical therapeutic method in the multidisciplinary care of non-small cell lung cancer (NSCLC) patients. However, radiation resistance continues to be a significant clinical issue, negatively affecting cancer prognosis in patients. The small molecules that target these RNAs offer therapeutic modulation of multiple biological processes. The study aims to identify the genes and a long non-coding RNA (lncRNA) regulating their expression and binding potential of small volatile inhibitors to the lncRNA to overcome radioresistance in NSCLC. Methods: The non-coding RNA microarray dataset of NSCLC cells was analysed to identify the differentially expressed genes regulated by lncRNA driving radioresistance. The study comprises three volatile ligands due to their good pharmacokinetic profile to target the identified lncRNA. Results: The analysis revealed the dysregulation of the cell cycle, evasion of apoptosis and cancer immune response. A coexpression analysis with a network pharmacology approach revealed a lncRNA ENST00000605056 regulating three highly ranked hub genes. The molecular interaction studies uncovered their high binding affinity to its binding pocket with a preponderance of non-covalent bond interactions between the ligand and the nucleotides. The molecular dynamics simulations revealed the binding stability of ligands to the lncRNA with a very low deviation compared to the control. Conclusion: This study demonstrated the ability of the small molecules to target lncRNA in overcoming the global concern of radioresistance among NSCLC patients and aid in future translational studies.